Developing a highly potent anthelmintic: study of catalytic application of l-proline derived aminothiourea in rapid synthesis of biscoumarins and their in vitro anthelmintic essay

Article abstract of DOI:10.1007/s12039-020-01881-3

Abstract: Due to serious side effects of benzimidazoles such as apoptosis and mitotic arrest, development of alternative anthelmintic drugs with comparable efficacy to target the acetylcholine receptors of parasites is considered very important to control

Full text of DOI:10.1007/s12039-020-01881-3

J. Chem. Sci. (2 0 2 1 ) 13 3: 16
Ó In di an Aca dem y of Sc i en c es
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REGULAR ARTICLE
Developing a highly potent anthelmintic: study of catalytic
application of L-proline derived aminothiourea in rapid synthesis
of biscoumarins and their in vitro anthelmintic essay
a
BA L AM P HR AN G K HA R RN GI , ER RI NI DEC RUS E DHAR , GR ACE B ASUM ATAR Y ,
b
a
c
DHAR ITR I DAS , RAM E SH CH DEKA , AR UN K YADAV a nd GHANAS HYAM B EZ
c
b
a ,*
a
De p ar tm e nt o f Ch em is t r y, N or th- E as t ern Hi l l Un ive rs i t y, S hi l lon g, Meg ha l aya 793 022, In di a
De pa rt m en t of Zo ol og y, N or th- Ea s t er n Hi l l Un ive r s i ty , S hi l lon g, Meg ha l aya 793 022, In di a
De p ar tm e nt o f Ch em ic a l S cie nc es , Tezp ur Un ive r s i ty , Nap aam , Te zpu r, As s am 784 028, In di a
b
c
E- ma i l: gh an as hy am be z@ ya ho o. com ; bez @ neh u.a c.i n
MS r ecei v ed 5 A u gu s t 2 02 0 ; r ev i s ed 9 No v em b er 2 0 2 0; accep t ed 2 9 N o v em ber 2 0 2 0
Abstract. D ue to s er io us s id e ef f ect s of ben zim i dazo les s uch as apo pt os i s and m i to ti c arr es t , dev el op me nt o f
a lt e rn at iv e an th el m int ic d r ug s w ith com par abl e effi c acy t o t arge t t he acet yl cho li ne rec ept o rs o f par a si t e s i s
c o ns i d er ed ve ry im p or t an t to co nt r ol t hi s par as i ti c di s eas e . Her e we hav e dev elo ped an exc ell ent m e th o d f or
s y n t he s i s of bi s co um ar in s by em p lo y i ng a m i ld and effi c ien t pr ol ine der iv ed bi f unc ti on al t hi oure a c at a l y st
b e ari n g py r r ol id in e an d th io ur ea ca ta l yt i c s i te s and t es t ed t hei r ant hel m i n t ic act i vi ty aga in st hel m i nt h p ar a-
s i t es Raillietina echinobothrida an d Syphacia obvelata. The com pou nds 2a, 2j, 2k and 2o dem ons t r ated mu c h
s t ro n ge r an th el m int ic ac tiv it y ag ai ns t Raillietina echinobothrida i n com p ari s on t o t he s t andar d dr ug , Pr a zi -
q u an t el . Mo le cul ar do ck i ng s im u l at io ns of t he opt i m i zed com p o und s wi t h b-t ub uli n s how ed exc ell ent b in d i ng
i n t er a ct io ns w ith s ev er al am i no ac id res i du e s of t he act i ve s i te and t he doc ki ng s cor es wi t h b-t ub ul i n we re
fo u n d to be co m pa ra bl e to th e in vitro ant hel m i nt ic act i vi t y.
Keywords. L- Pr o li ne th io ur ea ; bi s co um ari n; ant h el m i nti c; Raillietina echinobothrida; doc ki ng.
1
. Introduction
be nz im ida z ole s ha ve sho wn se r iou s si de e ff e ct s s uc h
de ve lo pme nt of
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He lm in t h in f e c tio n , a ma jo r pa ra si t ic di s ease th at
a ffe c ts mi ll io n s o f pe op l e on t he ea rt h , o ft en da m ag e
b l o od v e s s e ls le a d i ng t o l iv er , ey es , ur i na ry t ra c t, e tc .
Al t h o u g h th e h e lmi n th i nf ec ti o ns ar e l oc al i zed m ai nly
i n th e in t e s tin a l tra ct , t he y ca n en t er t he bl o od c ir c u-
l a ti o n , h e a rt, li v er , l un gs an d mu sc le s. I dea ll y, th e
a n t he lm in t ic d ru g s ar e de si g ned t o ex t er mi na te th e
h e l m in th s fro m th e ho st or g ani s m by d ama gin g of
n e u ro mu s c u la r c oo rd i na ti on of t he he l mi nt hs, th ei r
e n e rg e tic p ro c e s s e s an d en zy ma ti c sy st e m, l a ying of
e g g s , e tc . He lm in th pa ra si t es em pl oy ac et yl ch oli ne
e ffi c ie nt dr ug s wit h c om pa ra bl e e ffi c a cy to b en zi mi-
da z ole s to ta r ge t th e a ce ty lc hol ine r ec e pt or s of pa r a -
si te s is c onsi de r ed ve r y im por t an t to c ont ro l of this
pa r as iti c di se ase .
C oum ar i n or 2 H- ch r ome n- 2 -o ne is a ‘ pr ivil eg ed ’
st ru ct ur al m oti f wit h di ve rs e ph ar m ac o logic a l
4
r es um e. Am ong th e c oum a ri n de r iva ti ve s, bis -
c oum a ri ns ha ve de m onst ra t ed un ique bi ol ogic a l
5
–
9
1
0
,
1
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pr op er ti es suc h a s a nti ca nc e r ,
1
e nz ym e in hibi tor y a ct ivi ty,
a nti co ag ula nt,
a nti oxi dant ,
1 8 – 2 0
I n a ddi tio n, the y
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a nti mi cr ob ia l, a nd m an y m or e.
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re s p o n d to it . Al th ou gh ma ny dr u gs t ar ge tin g th e a ce ty lc hol ine e ste r a se in hibi tor y a ct ivi ty of c ou ma r in
a cet y lc h o l in e re c e pt o r ar e de ve l op ed, t he ir ef fi ca c y is ba se d un sym me tr i ca l tr i subst itu te d m et ha nes a s a
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Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-020-01881-3) contains
supplementary material, which is available to authorized users.

1
6
Pa g e 2 o f 1 5
J. Chem. Sci. (2 021) 1 33: 16
2
d i s ea s e . S in c e i nh ib i ti on o f ac et yl c ho li n e r ec e pt or s a ct iva te th e sub str a te s be a ri ng a nio ns a nd c a r bonyl
4
4
1 – 4 8
a re o n e o f th e ma j or mo de s of ac t io n o f an t hel mi nti c gr ou ps th ro ugh dou ble - hyd roge n bon din g.
d ru g s , we e mp l oy ed t ho se un sy mme t ri c al t r isub sti - R ec e ntl y, we ha ve obs er ve d th at L - pr oli ne de r ive d
4
9 ,5 0
t u t e d me t h a n e s (A, Fi g ur e 1 ) f or t re at me nt a ga ins t bi fu nc tio na l a mi dot hiou r ea
c at al yz e d syn the s is of
h e l m in th p a ra s ite s , Raillietina echinobothrida a nd bi s( ind olyl ) me tha ne s via a nuc l eo phil ic a ddi ti on- su b-
Syphacia obvelata an d no t ed t ha t so me of t h e c om - st itu tio n pa th way r at he r th an th e c onve nt ion al r oute ,
p o u n d s d e mo n st rat ed b et te r ac t iv i ty t ha n co m mon ly i.e ., by a dom in o Kno eve na ge l –Mic ha el r e a ct ion
u s e d a n th e lm in t ic d ru gs su ch as al b en daz o le whi ch is pa th way . Thi s ne w pa th way ha s th e po te nti al to ge n-
v e ry s ig n i fi c an t fo r a dr u g i nh ib i ti ng t he ac et yl c hol ine e ra t e a sym me tr i c tr i subst itu te d m et ha ne s unde r the
re c e p to r. Gi v en t he p or tf ol i o of b is co uma r ins , we op tim iz e d c ondi tio ns. Giv en th e gr owi ng a ppl ic a tions
5
1 – 5 3
p ro p o s e d to s tu d y t he ef f ect of t he pr es en ce of two of L- pr oli ne a nd it s de r iva ti ve s in or ga noc a ta lys is
c o u m ar in u n it s in a sy mme t ri cal t ri su bs t it ut e d me tha ne a nd ou r r ec e nt fi ndi ng on th e e ffi c a cy of th e c at a lys t in
s y s te m . c ar bo n–c a rb on bon d- f or mi ng r ea c ti ons, we pl a nne d to
M a n y h o mo g en eou s an d he t er og en eou s ca ta ly sts a ppl y th e c at al yst 1 f or th e m ult ic om pone nt synt he sis
u n d e r v a ry in g re ac t io n co nd i ti on s ar e r epo r te d to c at - of th e pr op ose d bi sc oum ar i n c om poun ds ( Sc h e me 1 )
a l yz e th e s y n th e s is of co um ar in ba se d sy mme tr ic a l a nd st udy th ei r a nth el mi nti c a ct ivi ty. Our st udy le d to
t ri s u b s ti tu te d me t h an es by a mu lt i co mp on ent re a ct ion th e de ve lo pme nt of a n e xtr e me l y e ffi c ie nt pr ot oc ol f or
o f a ld e h y d e wi th 4 - hy dr ox yc ou mar i ni n t he p rese nc e of th e syn the si s of bi sc oum ar i n und er e nvi ro nm e nta lly
25 –40
a h o s t o f a ld e h y d es .
M os t of t he r epo r te d m et hods be ni gn m ult ic om pone nt r ea c ti on c ondi tio ns in w at er
e m pl o y a c id c a ta l ys is t o af f ect t hi s t ra ns fo rm a tio n. m ed ium be r ef t of a ny or ga ni c sol ve nt a nd c hr oma to-
Ge n e ra lly , a c id -c at a ly ze d r eac t io ns ar e of t en di ffi c ult gr a phi c pur i fic a tio n.
d u e to th e i r p o o r f un ct io na l g ro up co mp at i bi l i ty, sus -
c ep ti b ili ty to w a rd s mo is t ur e an d ai r , an d ha za rdo us to
2
2
2
. Experimental
h a n d le . In in d u s t rie s, ac i d ca t al ys ts da ma ge t he pl an t
t h r o u g h th e i r c o rro si ve ne ss an d l ea d t o l ar ge vo lum es
o f t o x ic a n d c o rro si ve was t es. Th er ef or e, t he use of
o rg a n o th i o u re a a s a mi l d al t er na t iv e t o Le wis / Br onst e d
a ci d s h a s ta k e n a g rea t st r id e i n r ece nt y ear s. Esp e-
c i al ly , th e b if u n c ti on al t hi ou r eas ha ve f ou nd nu me r ous
a p p li c a tio n s a s o rg ano ca t al ys ts du e t o t he ir ab il ity to
.1 Chemistry
.1 a General. Unl es s ot he rwi se m en tio ne d, a ll the
c he mi ca ls a nd r ea ge nt s we r e a va ila bl e c om me r c ia lly
a nd we r e use d wit hout f ur the r pur i fic a tio n. Th e pr od-
1
1 3
uc ts we r e c ha ra c te r iz e d by I R, H NMR , C N MR .
The I R spe c tr a we r e r ec or de d on a P er ki n Elm er
1
spe c tr op hoto me ter . H NMR ( 400 MHz ) a nd
1 3
C
NMR ( 100 MHz ) spe c tr a we r e ob ta ine d on a B r uke r
Ar
OH
O
NH2
N
N
AC -4 00 usi ng C DCl a s sol ve nt a nd TM S a s a n
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f oll owin g th e m et hods r ep or te d by B as uma ta r y et al.
.1 b General procedure for the synthesis of bis-cou-
marin. A sus pe nsio n of th e a lde hy de ( 0.5 mm ol) ,
- hy dr oxy c oum a ri n ( 1 m mol ) a nd th e c ata ly st 1
O
2
(
A)
4
Figure 1. Po t e n t an th elm i nt ic ag ai ns t Syphacia obvelata. ( 10 m ol%) in H O ( 5 m L) in a 50 m L r oun d bott om
2
OH
R
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Ph
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O
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OH
N
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(10 mol%)
H O, reflux, 15-45 min
O
2
O
O
Scheme 1. O r gan ocat a l yt ic s ynt hes i s of bi s coum ari ns .

J. Chem. Sci. (2 0 2 1 ) 13 3: 16
P age 3 of 15 16
fla sk fi tt ed wi th co nd en se r was p la ced i n a he a tin g ( 411 m g) ; M. p. 21 8–220 °C ( 217 –219 °C ); Rf = 0.5
m a nt le a n d h e a ted t o r eflu x. Th e pr o gr es s of th e ( EtOAc /H ex :7.5 /2.5 v/ v) ; I R ( KBr ) : 30 75, 272 9, 1666 ,
-
1 1
re a c ti o n wa s mo n i t or ed by TL C. Af te r co mp le ti on of 109 4, 76 5 c m ; H NMR ( 400 MHz , C DCl ) d 3.79
3
t h e re a c ti o n , th e rea ct i on mi xt u re was co ol e d t o r oom ( s, 3H) , 6.0 4 ( s, 1H, –C H) , 6.8 6 ( d, J = 8.8 Hz , 2H ) ,
t e m p e ra tu r e to o bs er ve t he f or mat i on of t he pr e ci pi- 7.1 3 ( d, J = 8 Hz , 2H,, Ar H) , 7.3 9–7.4 1 ( m, 6H, A rH ),
t a te . T h e p re c ip it at e was t he n was he d wi th wa te r 7.6 0–7. 64 ( m, 1H, Ar H) , 8.0 0–8. 05 ( m, 1H, Ar H) , 11.3
1
3
(
2 9 5 mL ) a n d et h an ol ( 2 9 5 mL ) t o r emov e a ny ( s, 1H, Ar - OH), 11 .5 ( s, 1H, Ar - OH) ppm ; C N MR
re s id u al u n re a c te d st a rt i ng ma te ri a ls an d t he c at al yst . ( 100 MHz , C DCl ) : d 35. 7, 55 .5, 10 4.4, 10 6.0, 114.2 ,
3
Th e p re c ip i ta te was t he n r ecr ys t al li s ed f ro m et ha no l to 116 .8, 124 .6, 125 .1, 12 7.1, 12 7.8, 13 3.0, 15 2.5, 152.7 ,
o b t ai n a h ig h l y p u r e p ro du ct i n ex ce ll e nt yi e ld .
158 .6, 164 .8, 165 .9, 169 .5 pp m; ES I -M S ( m/z) : 465
?
?
[
M ? Na ] , 44 3 [ M ? H] ; Ana l. c al c d. f or
C H O ( 442 .10 g/ mol ) : C , 70. 58; H, 4.1 0; f o und: C ,
2 6 1 8 7
0
2
men-4-one). W hi t e so l id ; Yi el d: 96 % ( 39 6 mg) ; M. p.
. 1 c 3,3 -(Phenylmethylene)bis(2-hydroxy-4H-chro-
2
7
7
0. 57; H, 4.0 9.
2
3
7
–
3 0 – 2 3 2 °C (2 2 8 – 2 30 °C) ; Rf = 0. 5 ( Et OAc/ He x: 6.8 /
0
. 8 v /v ) ; IR (KB r) 3 449 , 30 7 8, 1 674 , 16 1 3, 10 99, 2.1 g 3,3 -((3,4-Dimethoxyphenyl)methylene)bis(4-hy-
3 0
-1 1
5
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C olou rl e ss pow de r ;
CH ), 7 .2 1– 7. 4 2 ( m, 11 H, ArH) , 7 .61 –7 .65 ( m, 1H, Yie ld : 90 % ( 425 m g) ; R f: 0.3 5 ( n- He xan e/ EtOA c : 1/9
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6 . 4 , 1 1 6 . 9, 1 2 4 . 8, 1 25. 1, 12 6 .7, 1 27. 1, 12 8 .9, 133 .1,
3 5 . 4, 1 5 2 .5 , 1 5 2 . 8, 1 64. 8, 1 66. 0, 16 7 .1 pp m; E SI - MS OC H ) , 3.6 7 ( s, 3H,- OC H ) , 5.1 4 ( s, 1H, –C H–) , 6.19
H NMR ( 400 MHz , DMS O- d6) : d 3.5 0 ( s , 3H ,-
3
3
?
?
(
m/z): 4 3 5 [M ? Na] , 4 13 [ M ? H] . An al . c al cd . ( s, 1H) , 6.6 4–6.6 1 ( m, 2H) , 6.7 4 ( d, J = 7.9 H z, 1H ) ,
fo r C H O (4 1 2.3 9 g/ mo l ): C, 7 2.8 1; H, 3.9 1; 7.2 5–7. 20 ( m, 4H) , 7.5 0 ( t, J = 8.5 Hz , 2H) , 7 .80 ( d,
2
5 1 6 6
1
3
fo u n d : C, 7 2 . 80 .7 2; H, 3. 92 .
J = 8.5 Hz , 2H) , 17 .59 ( s, 1H) ppm ; C N MR
( 100 MHz , DMS O- d6) : d35 .7, 55. 4, 57 .5, 103.6 ,
111 .5, 115 .4, 118 .8, 11 9.9, 12 2.8, 13 0.8, 13 4.9, 146.5 ,
0
2
. 1 d 3,3 -(p-Tolylmethylene)bis(2-hydroxy-4H-chro-
3
0
men-4-one)). Wh i te so l id ; Yi el d 9 2% ( 39 2 m g) ;
M . p. 2 6 7 – 2 6 8 °C ( 26 8– 26 9 °C) ; Rf = 0. 6 (Et OAc /
He x : 8 /2 v /v ) ; IR ( KBr) ; 3 050 , 29 9 5, 2 915 , 16 73,
6 0 8 , 1 0 9 3 , 7 6 4 c m . H NM R ( 40 0 M Hz, CDC l ) d
. 3 3 (s , 3 H), 6 . 06 ( s, 1H , –C H) , 7. 11 ( m, 4H, Ar H) ,
. 4 1 –7 .4 0 (m , 4 H, Ar H) , 7. 64 –7 .0 6 ( m, 2H , Ar H ), 8.0 6
1
48 .1, 152 .4, 164 .5, 168 .0 pp m; ES I -M S ( m/z) : 495
?
M ? Na ] , 47 3 [ M ? H] ; Ana l. c al c d. f or
C H O ( 472 .11 g/ mol ) : C , 68. 64; H, 4.2 7; f o und: C ,
?
[
-1 1
2
7
2
0
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1
2
7
3
6
8
.
6
4
;
H
,
4
.
2
8
.
0
2.1 h 3,3 -(Benzo[d][1,3]dioxol-5-ylmethylene)bis(2-
hydroxy-4H-chromen-4-one).
3
0
(
m , 2 H, Ar H), 1 1 .2 ( s, 1 H, Ar -OH) , 1 1.5 ( s, 1 H, Ar -
1
W hi te sol id; Y ie ld
3
OH ) p p m; C NM R ( 10 0 M Hz, CDC l ) d 21 . 8, 36. 7,
3
94% ( 429 m g) ; M. p. 25 6–257 °C ( 254 –25 7 °C ) ;
R f = 0.6 ( EtOAc /H ex : 8/ 2 v/ v) ; I R ( KBr ) : m 3445 ,
1
1
4
0 6 . 6, 1 1 7 .5 , 1 2 5 . 2, 12 5 .7, 12 7 .2, 13 0 .2, 13 2 .9, 13 3.7,
3 7 . 3, 1 5 3 . 1, 1 5 3 . 4, 1 65. 4, 16 6 .6 pp m; ES I- M S ( m/z) :
-1 1
89 8, 16 60, 161 3, 110 0, 10 39, 765 c m ; H N MR
2
?
5 9 [M ? Na ] , 42 7 [ M ? H] ; An al . ca l cd . f or
?
( 400 MHz , C DCl ) : d 5.9 3 ( s, 2H) 6.0 1 ( s, 1H , –C H ),
6.7 4–6. 67 ( m, 3H, Ar H) , 7.4 0 ( m, 4H, Ar H) , 7.62 ( t,
3
C H O (4 2 6 . 1 1 g/ mo l ): C, 7 3.2 3; H, 4 .25 ; f oun d: C ,
2
6
1
8
6
7
3 . 21 ; H, 4 .2 6.
J = 8 Hz , 2H, Ar H) , 8.0 4 ( m, 2H, Ar H) , 11 .2 ( s , 1H ,
1
3
0
Ar - OH), 11 .5 ( s, 1H, Ar - OH) pp m;
C N MR
2
. 1 e 3,3 -((4-methoxyphenyl)methylene)bis(4-hydroxy-
W hi t e so l id ; Yi el d 95%
3
4
( 100 MHz , C DCl ) : d 36 .1, 10 1.4, 107 .4, 10 8.5, 116.8 ,
3
2H-chromen-2-one).
1
1
19 .8, 124 .6, 125 .1, 12 9.1, 13 3.1, 14 6.7, 14 8.4, 152.7 ,
64 .8, 16 5.9, 167 , 16 9.4 ppm ; ES I -M S (m/z) : 479
(
(
4 2 0 mg ) ; M .p . 2 47– 2 49 °C ( 24 7– 24 9 °C) ; R f = 0.5
E t O Ac/ He x : 8 /2 v /v ); I R ( KBr) : 34 5 2, 3 072 , 167 2,
?
?
-1
[ M ? Na ] , 45 7 [ M ? H] ; Ana l. c al c d. f or
C H O ( 456 .08 g/ mol ) : C , 68. 42; H, 3.5 3; f o und: C ,
1
6 1 1 , 1 5 6 3 , 1 5 0 7 , 14 5 1, 1 350 , 13 0 7, 1 256 , 76 0 c m ;
1
H NM R (C DCl ) : d3. 83 ( s, 3 H, CH O) , 6. 08 ( s, 1H,
2 6 1 6 8
3
3
68. 40; H, 3.5 5.
C H), 6 . 87 –8 .0 8 (m , 12 H) , 1 1.3 2 ( s, 1H , O H) , 1 1.54 ( s,
1
3
1
1
H, O H) p p m; C NM R ( CDCl ) : d 35 .5 , 55 .2 , 114 .0,
0
3,3 -((3-Nitrophenyl)methylene)bis(2-hydroxy-
3
2.1 i
4H-chromen-4-one) .
(
3
6
1 6 . 6, 1 2 4 . 3, 1 2 4. 8, 1 26. 9, 1 27. 6, 1 32. 7, 1 58.4 pp m;
?
W hi te sol id; Yie ld 97%
443 m g) ; M. p. 238 –24 0 °C ( 238 –239 °C ); R f = 0.6
EtOAc /H ex : 8/ 2 v/ v) ; I R ( KBr ) : m 306 9, 27 28, 1672 ,
?
ES I -M S (m/z): 4 6 5 [ M ? Na] , 44 3 [ M ? H] ; Ana l.
c al c d . fo r C H O ( 44 2.1 0 g/ mo l ): C, 70 .5 8; H, 4.1 0;
fo u n d : C, 7 0 . 54 ; H, 4 .13 .
2
6 1 8 7
(
-1 1
1
10 7, 76 2 c m ; H NMR ( 400 MHz , C DCl ) : d 6.12
3
0
( s, 1H, –CH) , 7.5 8–7. 38 ( m, 6H, Ar H) , 7.6 6 ( m, 2H ,
ArH) , 8.0 0 ( d, J = 8 Hz , 1H, Ar H) , 8.0 9–8. 06 (m , 2H ,
2
4
. 1 f 3,3 -((2-Methoxyphenyl)methylene)bis(2-hydroxy-
W hi t e so l id ; Yi el d 93%
30
H-chromen-4-one).

1
6
Pa g e 4 o f 1 5
J. Chem. Sci. (2 021) 1 33: 16
ArH ), 8 . 15 (d , J = 8 Hz, 1 H, Ar H) , 11 .3 ( s, 1H, Ar - He xa ne /Et OAc: 1/ 9 v/ v) ; M. p. 215 –21 6 °C ( 215–2 16
13
OH) , 1 1 . 5 (s , 1 H, Ar -OH) pp m; C NM R ( 100 MHz , °C ); R f = 0.5 ( EtOAc /H ex : 8/ 2 v/ v) ; I R ( KBr ) : m 3401 ,
-1 1
C D Cl ): d 3 6 .4 , 10 4 .8, 1 17. 1, 12 2 .0, 12 2 .4, 12 4.74, 308 5, 16 62, 163 1, 15 77, 127 5, 11 09, 774 c m ; H
3
1
1
4
2 5 .4 , 1 2 9 . 8, 1 3 3 .0 , 13 3 .6, 13 8 .2, 14 8 .9, 15 2 .5, 15 2.8, NMR ( 400 MHz , C DCl ) : d 6.0 2 ( s, 1H, C H ),
3
?
6 7 .2 , 1 6 9 . 4 p p m ; ES I- M S (m/z) : 48 0 [ M ? Na ] , 6.8 0–7. 65 ( m, 12 H, Ar H) , 7.9 8 ( s, 1H, OH) , 8 .05 ( s ,
?
1 3
5 8 [M ? H] ; An al . ca l cd. f or C H NO
8
1
H
,
O
H
)
p
p
m
;
C
N
M
R
(
1
0
0
M
H
z
,
C
D
C
l
3
)
d
3
6
.
1
,
25
1 5
(
4 5 7 . 0 7 g /m o l): C, 6 5.6 5; H, 3 .31 ; N, 3 .06 f o und: C , 105 .7, 116 .4, 116 .6, 12 4.4, 12 4.8, 12 6.4, 12 6.8, 128.6 ,
128 .9 13 2.8, 13 5.1, 145 .1, 162 .9 pp m; ES I -M S ( m/z) :
6
5 . 62 ; H, 3 .3 0; N , 3. 09 .
?
53 [ M ? Na ] , 43 1 [ M ? H] ; Ana l. c al c d. f or
?
4
C H F O ( 430 .08 g/ mol ) : C , 69. 77; H, 3.5 1; f ound:
C , 69 .72; H, 3.5 4.
0
2
2
2
. 1 j
3,3 -(2-Nitrophenyl)methylene)-bis(4-hydroxy-
27
2 5 1 5
6
H-chromen-2-one). Yi el d: 95 % ( 43 4 mg ); M. p.
0 2 – 2 0 5 °C (2 0 2 – 2 05 °C) ; Rf = 0 .5 ( Et OAc/ H ex : 8/ 2
0
v / v ) ; IR (KB r): m 3 433 , 30 7 6, 2 722 , 16 5 2, 16 1 8, 15 61, 2.1 n 3,3 -((4-Bromophenyl)methylene)bis(2-hydroxy-
-
1
5 3 2 , 1 4 5 0 , 1 3 5 2 , 13 0 9, 10 9 9, 76 1 cm ; H NMR 4H-chromen-4-one).
1
2 7
1
W hi te sol id; Yie ld 93%
(
C D Cl ): d 6 . 64 ( s, 1 H, CH) , 7 .27 –8 .01 ( m, 12 H, ( 457 m g) ; M. p. 268 –26 9 °C ( r ef 266 –26 8 °C) ; R f =
3
H
13
Ar H), 1 1 .5 5 (b s , 2H , OH) p pm; C NM R ( CDCl ) : d
0.5 ( EtOAc /H ex : 7/ 3 v/ v) ; I R ( KBr ) : m 30 72, 2981 ,
-1 1
3 . 86 , 1 0 3 .7 1, 1 1 6. 66 , 12 4 .57 , 1 25. 03 , 12 8 .19 , 129 .49, 167 2, 160 7, 109 9, 765 c m . H NMR ( 400 M Hz ,
3
C
3
1
[
3 1 .9 4, 1 3 3 . 20 , 14 9 .76 p pm; ES I- M S ( m/z) : 48 1 C DCl ) : d 6.0 1 ( s, 1H, –CH) , 7.1 0 ( d, J = 7.6 H z, 2H ) ,
3
?
?
M ? Na ] , 4 5 9 [ M ? H] ; An al . ca l cd . f or 7.3 6–7. 44 ( m, 6H, Ar H) , 7.6 1–7.6 6 ( m, 2H, A rH ),
C H NO (4 5 7 . 3 7 g/ mo l ): C, 65 .6 5; H, 3. 31 ; N, 3.0 6 7.9 8–8. 07 ( m, 2H, ArH) , 11. 3 ( s, 1H, Ar - OH), 11.5 ( s ,
2
5
1 5
8
1
3
fo u n d : C, 6 5 . 64 ; H, 3. 32 ; N, 3 .10 .
1H, Ar - OH) ppm ; C NMR ( 100 MHz , C DC l ) : d
3
36. 1, 11 6.9, 121 .0, 12 4.7, 125 .2, 12 8.6, 131 .9, 133.3 ,
135 .7, 15 2.5, 152 .8, 16 4.9, 16 6.3, 167 .1 pp m; ES I - MS
0
2
2
.
1
k
3
,
3
-
(
2
-
H
y
d
r
o
x
y
p
h
e
n
y
l
)
m
e
t
h
y
l
e
n
e
)
-
b
i
s
(
4
-
h
y
d
r
o
x
y
-
35
H-chromen-2-one). White so lid , 9 0% y ie ld ( 385 mg) ;
M . p . 160– 161 °C (r e f = 1 60 – 25 4 °C) ; Rf = 0 .5 (Et OAc /
H ex : 6. 8/ 3. 8 v / v ) ; IR ( K B r ): m 34 41, 3075 , 1672, 1611,
?
m/z) : 51 4 [ M ? Na ] , 49 2 [ M ? H] ; Ana l. c a lc d.
?
(
f or C H B rO ( 490 .00 g/ mol ) : C , 61. 12; H, 3.08;
f oun d: C , 61. 09; H, 3.0 4.
2
5
1 5
6
-1
1
1
1
7
1
0
9
7
,
7
5
5
c
m
;
H
N
M
R
(
4
0
0
M
H
z
,
D
M
S
O
-
d
6
)
:
d
0
7
.
1
0
(
s
,
1
H
)
,
8
.
2
2
(
d
,
J
=
4
.
9
H
z
,
1
H
)
,
8
.
1
1
(
s
,
2
H
)
,
2
.
1
o
3
,
3
-
(
(
3
-
B
r
o
m
o
p
h
e
n
y
l
)
m
e
t
h
y
l
e
n
e
)
b
i
s
(
4
-
h
y
d
r
o
x
y
-
2
8
.7 3 (dd, J = 7.6, 2.1 Hz, 2H), 7.50 (dd, J = 7.9, 2.1 Hz, 2H-chromen-2-one). W hi te pow der . Yie ld: 94%
H), 7 . 4 6 –7 . 4 0 (m, 2 H) , 7 .2 1–7 .13 ( m, 4 H) , 7 .09 (d, ( 461 m g) ; M. p. 25 3–255 °C ( 253 –254 °C ); Rf = 0.5
J = 7 .9 Hz , 1 H ), 7. 04– 6 .9 8 ( m, 1 H) , 6. 2o (s , 1 H) p p m; ( EtOAc /H ex : 8/ 2 v/ v) ; I R ( KBr ) : m 34 06, 307 0, 1656 ,
13
-1
1
C N M R (1 0 0 MHz , DM SO- d 6): d 168. 0, 16 5. 0 , 16 19, 156 8, 127 0, 11 00, 76 1 c m ; H N MR
1
62 .35, 153. 0, 148. 8, 136. 2, 131. 3, 124. 6, 123. 3, 12 1.4 ,
(
(
(
C
D
C
l
?
D
M
S
O
-
d
)
:
d
6
.
4
1
(
s
,
1
H
,
4
H
)
,
7
.
1
4
–
7
.
9
5
3
6
1
m, 12H, Ar - H), 11. 26 ( s, 1H, OH) ppm ; C N MR
3
120 .8, 120. 5, 115. 9, 103. 8, 72. 7, 39. 9 ppm ; E S I-M S (m/
?
?
z) : 451 [ M ? N a] , 429 [M ? H] . An al . c al cd . fo r
C H O (4 28. 08 g/ mol ) : C, 7 0.09 ; H, 3 .7 6; f o un d : C,
1
0
0
M
H
z
,
C
D
C
l
?
D
M
S
O
-
d
)
:
d
3
5
.
4
,
1
0
3
.
7
,
1
1
5
.
9
,
3
6
2 5
16
7
11 6.6, 12 1.8, 12 3.8, 123 .9, 125 .5, 128 .8, 129 .1 , 129.9 ,
7
0. 11 ; H, 3. 77 .
1
5
3 2.1, 14 0.9, 15 1.9, 16 4.4, 16 5.3 ppm ; ES I -M S ( m/z ) :
?
1 4 [ M ? Na ] , 492 [ M ? H] . Ana l. c alc d. f or
?
2
.
1
l
4
-
(
B
i
s
(
2
-
h
y
d
r
o
x
y
-
4
-
o
x
o
-
4
H
-
c
h
r
o
m
e
n
-
3
-
y
l
)
m
e
t
h
y
l
)
-
30
C H B rO ( 490 .00 g/ mol ) : C , 61 .12; H, 3.0 8; f ound:
2 5 1 5 6
benzonitrile. W hite so lid ; Yie ld 9 6 % (4 2 0 m g ); M. p .
62 –26 4 °C (2 61–2 63 °C); Rf = 0.5 (EtOAc/Hex: 7/3
v /v ); I R (KB r ): m 307 1, 29 75, 222 6, 16 62, 161 4, 1095,
C , 61. 11; H, 3.0 7.
2
0
2.1 p 3,3 -((4-Chlorophenyl)methylene)bis(4-hydroxy-
2H-chromen-2-one). W hi te pow der . Yie ld: 97%
-1 1
2
7
790 cm ; H N M R ( 4 00 MH z, CD Cl ): d 6. 09 (s ,1H, –
3
CH), 7. 43–7. 35 ( m , 6 H, Ar H ), 7 . 61 – 7. 68 ( m, 4 H , A rH ),
(
(
433 m g) ; M. p.: 25 7–259 °C ( 258 –259 °C ); R f = 0.5
EtOAc /H ex : 8/ 2 v/ v) ; I R ( KBr ) : m 343 2, 30 71, 1667 ,
7
1
1
1
. 98–8. 08 (m , 2H, ArH ), 11. 35 (s, 1H , Ar -O H ), 1 1 .5 5 (s ,
H , Ar- OH ) ppm ; C NMR ( 1 00 MH z, CD Cl ): d 3 6 .7 ,
03 .4, 116. 4, 116. 94, 118. 9, 124. 7, 125. 4, 127. 7, 13 2.7 ,
33. 5 , 14 1. 5, 152 . 8 , 1 65 .0 , 1 66.6, 1 67.2 p pm ; ESI - M S
13
-1 1
3
161 8, 15 62, 128 1, 10 93, 766 c m ; H NMR ( C DC l ,
3
4
2
7
00 MHz ) : d 5.9 7 ( s, 1H, 4H) , 7.0 8 ( d, J = 8.0 H z,
H, Ar - H), 7.2 1 ( m, 2H, Ar - H), 7.3 4 ( m, 2H, A r- H ) ,
?
?
(m/z) : 460 [M ? Na ] , 438 [M ? H] ; An al . ca lc d. f or
C H NO ( 437 .0 8 g/ mol ): C, 71 .39 ; H , 3.4 6; N 3.20;
fo u nd: C , 71 . 40 ; H, 3. 45 ; N 3. 23.
.5 7 ( m, 2H, Ar - H), 7.9 1 ( m, 2H, Ar - H), 8.0 0 (m , 2H ,
1 3
2 6
15
6
Ar - H), 11. 24 ( s, 1H, OH) , 11. 46 ( s, 1H, OH) ppm ; C
NMR ( 100 MHz , C DCl ) :d 34 .74, 102 .63, 104.1 6,
3
1
1
1
1 5.29, 11 5.62, 12 3.35, 12 3.94, 126 .88, 126.9 3,
2 7.70, 13 1.64, 13 2.00, 13 2.82, 151 .23, 151.4 4,
?
6 3.57, 164 .96 ppm ; ES I -M S (m/z) : 470 [ M ? N a] ,
2
men-3-yl)methyl)-4-hydroxy-2H-chromen-2-on.
W h it e s o li d ; Yi el d: 95 % ( 40 8 mg ); Rf : 0.3 5 ( n-
. 1 m 3-((4-Fluorophenyl)(4-hydroxy-2-oxo-2H-chro-
3
2

J. Chem. Sci. (2 0 2 1 ) 13 3: 16
P age 5 of 15 16
?
4 8 [M ? H] ; An al . ca l cd. f or C H C lO
-1 1
16 11, 10 89, 76 4 c m ; H NMR ( 400 MHz , CD C l ) :
3
4
25
1 5
6
(
4 4 6 . 0 5 g /m o l): C, 67 .2 0; H, 3 .38 ; f ou nd : C, 67 .21; H, d 6.6 6 ( s, 1H, –CH) , 7.2 8–7.4 7 ( m, 10H,, A rH ),
3
. 4 0.
7.5 5–7. 63 ( m, 4H, ArH) , 7.7 2 ( d, J = 7.6 H z, 1H ,
ArH) , 7.8 5 ( m, 3H, Ar H) , 7.9 7 ( d, J = 7.6 Hz , 1H ,
ArH) , 8.1 3 ( d, J = 7.6 Hz , 1H, Ar H) , 11 .1 ( s, 1 H, A r-
0
2
. 1 q 3,3 -(2-Chlorophenylmethylene)-bis(4-hydroxy-
W hi t e so l id ; Yi el d : 96 %
27
2H-chromen-2-one).
1 3
OH) , 11 .4 ( s, 1H, Ar - OH) ppm ; C NMR ( 100 M Hz ,
C DCl ) : d 35 .4, 10 7.6, 116 .8, 123 .0, 12 4.7, 125.2 ,
(
4 2 8 mg ) ; Rf : 0 .4 5 (n- Hex ane / Et OAc: 2/ 8 v /v) ; M. p.
0 2 – 2 0 4 °C (2 0 3 – 20 4 °C) ; Rf = 0. 5 ( Et OAc/ H ex 8/ 2) ;
IR ( KBr): m 3 0 6 9 , 27 2 0, 16 4 9, 15 5 6, 1 498 , 1 444, 13 40,
3
2
12 5.8, 12 6.5, 12 8.8, 129 .6, 131 .0, 131 .4, 133 .1 , 134.6 ,
1
5 2.4, 152 .7, 16 4.8, 165 .3, 167 .2, 16 9.2 ppm ; E SI - M S
-
1 1
1
C H ), 7 . 27 –8 .0 4 ( m, 1 2H, Ar H), 10 .9 3 ( s, 1 H, OH) ,
1
1
1
4
0 9 7 , 7 6 0 c m ; H NM R ( CDCl ) : d 6. 16 ( s, 1H,
?
m/z) : 485 [ M ? Na ] , 46 3 [ M ? H] ; Ana l. c a lc d.
?
3
(
f or C H O ( 462 .11 g/ mol ) : C , 75. 32; H, 3.92;
f oun d: C , 75. 29; H, 3.9 0.
13
2 9 1 8 6
1 . 6 4 (s , 1 H, OH) pp m; C NM R ( CDCl ) : d 35. 72,
3
1 6 . 59 , 1 2 4 .4 2, 12 4 .87 , 12 6 .76 , 1 28. 59 , 12 9.24,
3 0 . 81 , 1 3 2 . 83 , 13 3 .49 , 1 62. 33 pp m; ES I- M S ( m/z) : 2 . 1 u 3,3 -(Butane-1,1-diyl)bis(4-hydroxy-2H-chromen-2-
0
?
?
3 4
7 0 [M ? Na ] , 44 8 [ M ? H] ; An al . ca l cd . f or one). Wh i t e so li d; Yi el d: 89 % (3 36 m g ); R f: 0 .3 5 ( n-
C H Cl O (4 4 6 .0 5 g/ mo l ): C, 67 .2 0; H, 3 .38 ; f oun d: H ex ane / E t OAc (1 / 9 ). M. p . 1 1 8– 1 20 °C (119–1 23 °C);
2
5
1 5
6
C , 6 7 .2 4; H, 3 . 41 .
R f = 0.5 ( EtO A c /H ex : 8 /2 v/v ); I R ( K Br ) : m 3400 , 3 07 4,
1
-1 1
650, 1620, 1565, 1266, 1100, 765 c m ; H NMR
0
2
hydroxy-4H-chromen-4-one).
. 1 r 3,3 -((4-Chloro-3-nitrophenyl)methylene)bis(2-
W hi t e so l id ; Yie ld
(
DM S O- d6): d 0. 90 ( t , C H ), 1 . 2 5–1 . 31 (m , CH ) , 2 . 1 3
2
9
3
2
(
q , J = 7.2 Hz, CH ) , 4. 96 ( d, J = 8.0 Hz, CH),
2
9
7 % (4 7 6 mg ) ; M .p . 25 0 –25 2 °C ( 24 9– 25 1 °C );
7. 38–7 .41 ( m , Ar H) , 7. 63 ( t, J = 7. 2 H z, A rH ), 7 . 9 9 ( d ,
J = 7 .2 Hz , Ar H ), 1 1 . 97 (b r s , 2 H, O H) p pm ; ES I -M S
R f = 0 . 6 (E tO Ac/ He x: 8/ 2 v/ v ); I R ( KBr) : m 34 45,
-1 1
2
7 2 4 , 1 6 6 5 , 1 6 1 2 , 15 6 0, 13 5 1, 1 098 , 7 89 cm ; H
?
m/z): 401 [M ? N a] , 3 79 [M ? H ] ; Ana l. c alc d. f or
?
(
C H O (3 78 . 11 g/ mol ): C, 6 9. 83 ; H , 4 .7 9 ; fo un d : C ,
NM R (4 0 0 M Hz, CDC l ) d 6 .05 ( s, 1 H, –C H) ,
3
2 2 18 6
7
. 5 1 –7 .3 7 (m , 6 H, Ar H) , 7. 65 –7 .7 1 ( m, 3H , Ar H ), 8.0 0
d , J = 8 Hz , 1 H, Ar H) , 8 .09 ( d, J = 7. 6 Hz , 1H,
ArH ), 1 1 . 38 (s , 1 H, Ar -OH) , 1 1.5 8 ( s, 1H , Ar - OH)
6 9. 79 ; H , 7. 76 .
(
1
3
p p m ; C NM R ( 10 0 M Hz, CDC l ) d 3 6.0 , 10 3.2,
3
2.2 Biology
1
1
1 7 . 1, 1 2 4 .3 , 1 2 4 . 8, 12 5 .5, 13 1 .8, 13 2 .3, 13 3 .7, 136 .7,
4 8 . 3, 1 5 2 .6 , 1 5 2 . 8, 16 5 .1, 16 7 .1, 1 69. 3 p pm; ES I -M S 2.2 a Anthelmintic assay: Thi s st udy e mp loye d tw o
?
?
(
m/z): 5 1 5 [M ? Na] , 49 3 [ M ? H] ; An al. c al cd . spe c ie s
of
fo r C H Cl NO ( 49 1.0 4 g/ mo l ): C, 61 .0 5; H, 2.8 7; N echinobothrida ( a po ultr y ta pe wor m ) a nd Syphacia
he lm in th
pa r as ite s,
Raillietina
2
5
1 4
8
2
2
. 8 5 ; fo u n d : C, 6 1. 00 ; H, 2 .84 ; N 2 .90 .
obvelata ( a r ode nt pi nwor m ). R. echinobothrida w as
c oll ec te d f r om th e in te sti ne s of do me sti c f ow l tha t
we r e f r es hly sl au ghte r e d a t lo ca l a ba tto ir s a nd S.
obvelata wa s c oll ec te d f r om th e in te sti ne s of
la bo ra to ry - ma in ta ine d in fe c ti on in S wiss m ice . The
a dul t wor m s we r e c oll ec te d in 0.9 % ph osp ha te -
buf f e r ed sa li ne ( PB S ) a t 37 ± 1 °C a nd w as he d
se ve r al ti me s be f or e th ey we r e use d f or in vi tr o a ss a ys .
The wor m s we r e di vide d in th re e gr ou ps ( n = 5) a nd
m ai nta in ed in P et r i di she s c ont ai ning P BS a t 37 ± 1
0
. 1 s
3,3 -((3-Chloro-4-methoxyphenyl)methylene)-
bis(2-hydroxy-4H-chromen-4-one). W hi t e so l id ; Yie ld
3 % (4 4 3 mg ) ; M .p . 2 48– 2 50 °C ( NA); Rf = 0.6
9
(
1
E t O Ac/ He x : 7 . 5/ 2 .5 v/ v ); I R ( KBr) : m 34 4 9, 273 1,
-1
1
6 6 5 , 1 6 1 4 , 1 5 6 5 , 76 8 cm ; H NM R ( 400 MHz ,
C D Cl ): d 3 .8 8 ( s, 3H ), 6. 01 ( s,1 H, –CH) , 6 .88 ( d,
J = 8 .4 Hz , 1 H, Ar H) , 7. 08 ( m, 1H , Ar H) , 7 .18 ( s, 1H,
ArH ), 7 . 38 –7 .4 2 ( m, 4 H, Ar H) , 7 .63 ( m, 2 H, Ar H) ,
8
1
3
1
1
3
. 0 7 (m , 2 H, Ar H) , 11 .2 9 ( s, 1 H, Ar -OH) , 11 .56 ( s,
°
C in side a n in cu ba tor . Gr oup I a nd I I of w or ms
13
H, Ar- OH) p p m; C NM R ( 10 0 M Hz, CDC l ) : d
3
se r ve d a s a ne ga ti ve a nd a po siti ve con tr ol,
r es pe ct ive ly , whe r e th e f or me r r ec e iv ed on ly P B S
a nd th e la tt e r wa s gi ve n 800 lg/ mL of a r ef e r e nc e
dr ug , pr a zi qua nt el f or ta pe wor m s, a nd a lbe nd az ole in
c as e of ne m at ode s. Gr oup I I I of wor m s we r e exp ose d
to 80 0 lg/ mL c onc e ntr a ti ons of di ff e r en t bi sc ouma r in
c om poun ds. Obse r va ti ons we r e m ad e a t r e gula r
5 . 5 , 5 6 .4 , 1 0 4 . 0, 1 05. 5, 1 12. 2, 1 16. 9, 1 22. 9, 124 .7,
2 5 . 2, 1 2 6 .1 , 1 2 8 . 6, 1 33. 2, 1 52. 8, 1 54. 1, 1 64. 9 , 166 .2,
?
6 7 . 0 p p m; E SI -M S ( m/z) : 50 0 [ M ? Na] , 47 8
?
[M ? H] ;
(4 6 6 . 0 6 g /m o l): C, 65 .4 9; H, 3 .59 ; f ou nd : C, 65 .49; H,
An al .
ca l cd.
f
o
r
C H C lO
26 1 7 7
3
.
5
8
.
0
2
.
1
t
3
,
3
-
(
N
a
p
h
t
h
a
l
e
n
-
2
-
y
l
m
e
t
h
y
l
e
n
e
)
b
i
s
(
2
-
h
y
d
r
o
x
y
-
i
n
t
e
r
v
a
l
s
u
n
d
e
r
a
W hi t e so l id ; Yi el d 95% pa r al ysi s a nd m or ta lit y ti me of wor m s w er e
li ght m ic ro sc ope a nd the
32
4H-chromen-4-one).
(
(
4 3 9 mg ) ; M .p . 2 65– 2 66 °C ( 26 4– 26 5 °C) ; R f = 0.5 r ec or de d to a dju dge th e a nth el mi nti c pot enc y of
5 4
E t O Ac/ He x : 8 /2 v /v ); I R ( KBr) : m 34 4 9, 27 1 3, 166 1, c om poun ds.

1
6
Pa g e 6 o f 1 5
J. Chem. Sci. (2 021) 1 33: 16
2
. 2 b Statistical analysis: Th e ex pe ri me nt s we r e we r e e la te d wit h th e r es ult , we r ea so ne d th at if the
re p e a te d th r e e ti me s an d t he r esu l ts ar e r epr e se nte d r ea c ti on c an be c ar r ie d out un der ho mog en eo us r e a c-
a s me a n ± s ta n d a r d er r or o f t he me an ( SEM ) . Da ta ti on c ondi tio ns r at he r th an st ar t ing wit h a sus pe ns ion,
we re a n a ly z e d by o ne- way an al y si s of v ar i an ce th e r ea c ti on ti me c oul d f ur the r be r ed uc ed . The re f or e ,
(A N OVA), fo l lo wed b y t he Tu ke y t es t wi th p \ 0.0 5 we sc r ee n th e r ea c ti on wit h a hos t of ot he r solv en ts
c o n s id e re d a s s ta t ist i ca ll y si g ni fic an t . Al l t he st at ist ic al ( Ta ble 1) to obs er ve th at e tha no l ha s a lm ost s imila r
c al c u la ti o n s we re d one u si ng Or ig i n ve rs i on 8 .0 S R6 . e ffi c a cy a s a sol ve nt, whi le th e ot he r sol ve nts s uc h a s
m et ha nol , a ce to nit ri le , THF , a nd di et hyl e the r w er e
2
. 2 c Molecular docking simulation: I n ou r not a s e ff e c tiv e in c om pa ri son W e r ea so n tha t the
e x p e rim e n t, mo l ec ul ar d ock i ng st u di es of opt im um e ffi c a cy of th e r ea c ti on in wa te r me diu m
b i s co u m a ri n s ( 2a–2s) wi th b- tu bu li n wer e p erf or m ed m ight be du e to in cr e a se d io n c onc e ntr a ti on of wa te r a t
t o o b s e rv e b in d i n g af fin i ty an d ap pr op r ia te o ri e nta ti on hi gh te m pe ra t ur e a nd ‘‘ on wa te r ’’ r at e a cc e le r at i on. I on
?
o f th e c o mp o u n d s i ns id e t he pr o te in r ece pt o r by usi ng c onc e ntr a ti on ( H O a nd OH ) of wa te r in cr e a se s w ith
-
3
5
5
5 7
Au t o Do c k 4 . 2 pr o gr am.
i n t e ra c tiv e mo l e c u l ar gr ap hi c s p ro gr am em pl oye d to st an ce s wa te r m ay a ct li ke a bi fu nc tio na l c at al ys t tha t
Au to do ck 4 .2 is a n th e in cr e a se in te m pe ra t ur e. Und er suc h c ir c um-
56
i n v es ti g a te th e d ru g- pr ot ei n i nt er ac t io n. Th e c ry sta l c an a cc e le r at e th e r ea c ti on r at e by a ct iva ti ng the
s t ru c tu re o f b-t u bu li n ( PDB I D: 1 QSD) was o bta in ed e le ct r ophi li c a lde hy de a nd nuc l eo phil ic 4- hy dr oxy-
fr o m th e re s e a rc h co l la bo ra t or y f or st ru ct ur al c oum a ri n. Giv en th e f ac t th at th e r ea c ti on is ver y s low
b i o i n fo rm at i c s (R CSB) p ro te in d at a ba nk. The a t r oom te m pe ra t ur e r ea c ti on c ondi tio ns a nd did not
p ro t ei n s tr u c tu re i n pd b f or mat was t he n p r epa r e d gi ve c om ple te c onve r si on e ve n in 8 h, th e te m pe r a tur e
wi t h th e s tr u c tu re pr ep ar at i on t oo l av ai l ab le in Aut o a ide d r at e a cc e le r at ion due to in cr e a se d io nic str e ngth
Do c k T o o ls p a c k ag e ve rs i on 1 .5.4 . Al l t he wa te r is a c le ar pos sib ili ty. On th e ot he r ha nd, t he r a te
m o l e c u le s a n d th e na t iv e l ig an d ha d be en r em ov ed a cc e le r at ion of th e r ea c ti ons in wa te r m ed ium ma y be
fr o m th e c ry s ta l st r uc tu re of p ro te in an d t hen po la r due to ‘‘ on wa te r ’’ c ondi tio ns th at gi ve hi gh yie ld a nd
h y d ro g e n a to m s w er e ad de d f or sa t ur at i on , G ast e ige r f ew er si de pr od uct s whe n e ith er th e st ar t ing ma te r ia l,
5
8
c h a rg e s we re c o m pu te d an d no n -p ol ar hy d ro ge n a tom s pr od uct , or bo th a re r el a tiv el y in solu ble in wa te r .
we re me r g e d . A g ri d b ox was b ui lt wi th a gr i d spa c ing S uc h r at e a cc e le r at ion in a que ous sus pe nsi on a r e
-3
˚
o f 0 . 41 4 A a n d th e di me ns i on of 6 0 9 60 9 6 0 poi nts a ttr i bute d to hi gh he a t c ap ac it y ( 4.18 J c m K ),
a l on g x , y a n d z ax es ar ou nd t he ac t iv e si t e of th e hyd r oge n bon din g, c ha rg e st ab ili za ti on a nd dipo la r
5
9
p ro t ei n re c e p to r. Th i s gr i d b ox ca rr i es t he co m ple te e ff e c t of wa te r . S inc e th e r ea c ta nt s, pr od uct s a nd the
b i n di n g s it e o f th e ac t iv e si t e o f pr o te in and gi ve s c at al yst a re in solu ble in wa te r , ‘‘ on wa te r ’’ r a te
s u ffi c ie n t s p a c e f or t he t ra ns la t io na l an d r ota ti ona l a cc e le r at ion m ight ha ve he lp ed to r ed uc e th e r e a ct ion
m o ve m en t o f c om po un ds . Af te r t ha t t en p ossi ble ti me .
˚
d o c k in g ru n s we re pe rf o rme d wi th st e p si z es of 2 A
The c at al yst lo ad ing wa s a lso c he ck ed to obs e r ve
fo r tr an s l a tio n a n d 5 00 f or r ot at i on . A ma xim um th at 10 m ol% of th e c at al yst gi ve s opt im um yie ld
n u mb e r o f e n e rg y ev al u at io ns ar e se t t o 25 0 00 a nd a und er our r ea c ti on c ondi tio ns whi le in cr e a si ng the
m a xi mu m n u mb er of 27 0 00 GA op er at i on s we r e c at al yst lo ad ing to 15 m ol% a nd lo wer in g ti ll 5 mol %
g e n e ra te d wi th a n i ni t ia l po p ul at io n of 1 50 i nd ivi dua ls . we r e no t f oun d op tim um a s r efl e c te d in Ta ble 1 ( e n-
Th e ra te o f g e n e mu ta t io n an d cr os so ve r was se t to be tr i es 8– 10) . I n th e a bse nc e of th e c at al yst , th e re a c tion
0
. 0 2 a n d 0 .8 0, re sp ec ti v el y.
ga ve onl y 14 % yi el d up on he a tin g th e r ea c ti on m ixtur e
a t r efl ux in wa te r f or 1 h. The m ode l r ea c ti on w as a ls o
sc r ee ne d f or ot he r or ga noc a ta ly sts suc h a s bi fu nc tiona l
L- pr oli ne , H- bon ding c at al yst 1,3 -d iphe ny lt hiour e a ,
3
. Results and Discussion
3
. 1 a Chemistry. T he i nv es ti ga ti o n st a rt ed wi th st ir r ing pyr r ol idi ne a nd p- TsOH, a mo ng whi ch L- pr olin e ( En-
a s u s p e n s io n o f f re sh ly di s ti l l ed b enz ald eh yde tr y 12 ) sho wed m ax im um e ffi c a cy to gi ve 84% yie ld in
0 . 1 0 6 g , 1 mm o l ) wi th 4- h yd ro xy co uma ri n ( 0 .324 g, 150 m in of r efl ux in wa te r . An e qui mol a r m ixt ur e of L -
(
2
0
mm o l) in th e p res en ce o f t he ca t al ys t 1 (0 .03 g, pr ol ine a nd 1,3 -d iphe ny lt hiou r ea be a ri ng th e ca ta ly tic
. 1 mm o l) in wa t er un d er co nv en t io na l he a tin g a t si te a s th ose of th e c at al yst 1 wa s a lso f ound le s s
re fl u x te m p e ra tu r e. To ou r su r pr is e, t he r eac t ion wa s e ffi c ie nt in c om pa ri son a nd to ok th e sa m e ti me a s tha t
c o mp le te wi th in 15 mi n as i nd ic at ed b y t h in- la ye r of L - pr oli ne to gi ve sl ight ly hi ghe r yi el d ( Ent r y 16) .
c h ro ma t o gr a p h y ( TLC ) p la te an d ga ve 96 % is ola te d T h e r e f o r e , t h e m o d e l r e a c t i o n g a v e t h e o p t i m u m
y i e l d (0 . 3 9 6 g ) af t er r ecr ys t al li z at i on . Al th ou gh we e f fi c a c y u p o n h e a t i n g a t r e fl u x i n w a t e r m e d i u m

J. Chem. Sci. (2 0 2 1 ) 13 3: 16
P age 7 of 15 16
a
Table 1. Op t i mi z ati on of r eac tio n co nd iti on s .
OH
OH Ph
O
OH
O
O
Catalyst 1
H O , reflux
Ph
O
O
2
O
O
b
En t r y
So l v e nt s
Ca t (m o l% )
Tem p .
Ti m e/ m i n
% Yi e ld
1
2
3
4
5
6
7
8
9
H O
2
Et OH
M eO H
AC N
THF
1 ( 10 )
1 ( 10 )
1 ( 10 )
1 ( 10 )
1 ( 10 )
1 ( 10 )
1 ( 10 )
1 ( 15 )
1 ( 5)
R efl ux
R efl ux
R efl ux
R efl ux
R efl ux
R efl ux
R T
R efl ux
R efl ux
R efl ux
R efl ux
R efl ux
R efl ux
R efl ux
R efl ux
R efl ux
15
30
30
45
45
45
8
15
30
9 6
9 2
7 8
7 6
7 9
5 2
6 8
9 6
8 4
8 9
1 4
8 4
3 2
4 4
2 8
9 0
Di e t h y l et her
H O
c
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 ( 8)
–
L - Pr o li ne ( 10 )
1, 3- D ip he ny lth i our ea (1 0)
P y r ro li di ne ( 10 )
p- Ts O H ( 10 )
30
60
150
180
180
180
150
H O
2
L - Pr o li ne ( 10 ) ? 1, 3-d i phe nyl th i our ea(10 )
a
Rea ct i o n c o nd i t i on s : be nz a ld eh yd e ( 1 m m ol ) an d 4- hydr ox yco um ar i n (2 m m ol ).
I so l a te d y i el d .
b
c
Ti me i n h o u r.
f o r 1 5 m i n i n t h e p r e s e n c e o f 1 0 m o l % o f t h e o f 4 - h y d r o x y c o u m a r i n t o B3 f o r m e d t h e b i s -
c o u m a r i n d e r i v a t i v e .
c a t a l y s t 1.
Di ffe re n t s u b s ti tu t ed ar om at ic al d eh yd es wer e c on-
d e n s e d wi th 4 -h y d ro xy co uma r in un d er t he op tim iz e d
0
re a c ti o n c o n d it io n t o ac hi ev e 3, 3 - ar yl i den eb i s- 4- hy- 3.1 Biology
d ro x y c o u ma r in s in ex ce ll e nt y ie ld s wi th i n a v er y sho r t
re a c ti o n ti me (T a bl e 2) . Th e st r uc tu re of t he s e c om - The in vitro a nth el mi nti c te st s sho wed th at the te s t
1
p o u n d s wa s c o n fi rm ed by ma ss sp ec tr al , I R, H NMR c om poun ds a re c om pa ra ti ve ly m or e e ff e c tiv e a ga ins t
1
3
a n d CN M R a n al y se s. Th e na t ur e o f su bs t it ue nts on R. echonobothrida th an S. obvelata ( Fi gur e 2 ). W hile
t h e p h e n y l ri n g h as ha rd l y af f ect e d t he r eac t ion r at e c om poun ds sho wed e xc el le nt to m ode r at e ef fi c a c y
a n d y ie l d s . Du e to t he mi l d n at ur e of t he ca t al y st 1, th e a ga ins t R. echonobothrida, th ey we r e on ly m ode r a te ly
a ci d -s e n s i ti v e fu n c t io na l gr o up s su ch as OM e, C N a nd e ff e c tiv e a ga ins t S. obvelata, wit h on ly a f ew c om-
m e t h y le n e d i o x y wer e n ot af f ect e d an d g ave exc e ll en t pou nds th at sho wed e ffi c a cy c om pa ra bl e to a lbe nda -
y i e l d s . T h e a li p h at i c al d eh yd e was f ou nd t o be le ss z ole ( ABZ ). I t a lso e me r ge d out f r om th is st udy tha t
re a c ti v e a s e v id e n t f ro m t he r eac t io n of bu t yr al de hyd e a bout ha lf of th e te st ed c om poun ds pos se ss a be tte r
wi t h 4 -h y d ro x y c o u mari n t ha t t oo k 45 mi n f or c om - e ffi c a cy a ga ins t R. echonobothrida th an th e r e f er e nc e
p l e t e c o n v e rs io n t o g iv e 89 % yi e ld o f t he de si re d dr ug , pr a zi qua nt el ( PZ Q). Not ab ly, th e c ompo unds
p ro d u c t (E n tr y 1 9 ) .
p l a u s i b l e m e c h a n i s t i c r o u t e i s p r o p o s e d r obe nz a lde hyd e (2k) , 4- c ya nobe nz a lde hyde (2j) a nd
S c h e m e 2 ) . T h e c a t a l y s t 1 r e a c t s w i t h a l d e h y d e t o be nz a lde hy de s ( 2a) , to ok onl y a bout ha lf th e t ime f or
de r i ve d f r om 2- c h lo r obe n z a ld eh yd e ( 2o) , 4- fl uo-
A
(
g e n e r a t e t h e i m i n i u m s a l t A w h i c h u p o n n u c l e - pa r al ysi s a nd m or ta lit y th an th at of th e r ef e r enc e dr ug
o p h i l i c a t t a c k b y 4 - h y d r o x y c o u m a r i n f o r m s t h e P ZQ. Thi s st udy a lso r ev ea l ed th at th e st ru ct ur e of the
i n t e r m e d i a t e B1. I n t e r m e d i a t e B m a y u n d e r g o k e t o - c om poun ds pl ay s a n im por t an t r ole in r eg ula ti ng the ir
e n o l t a u t o m e r i s m t o f o r m e n e r g e t i c a l l y s t a b l e i n t e r - a nth el mi nti c e ffi c a cy .
m e d i a t e s B2 o r m a y f o r m B3 b y r e l e a s i n g t h e
I nit ia l te st ing of c oum a ri n, ur a ci l, bi sc oum ar in a nd
c a t a l y s t ( 1 ) . T h e 1 , 4 - a d d i t i o n o f a n o t h e r m o l e c u l e bi s- ur ac il sho wed th at , in pa r tic ul a r, th e bi sc ou ma r ins

1
6
Pa g e 8 o f 1 5
J. Chem. Sci. (2 021) 1 33: 16
a
Table 2. Sy n t h es is of bi s co um ar in s via S che m e 1
t/min Yieldb M.p./ C M.p.[ref.]
o
Entry Aldehyde
Product
Ph
OH
OH
O
CHO
15
96
230-232 228-230
[27]
1
O
O
O
2
a
CHO
OH
O
2
15
15
92
267-268 268-269
OH
O
[
37]
O
O
2b
OMe
CHO
3
OH
O
95
247-249 247-249
27]
OH
O
[
OMe
O
O
O
2c
CHO
OMe
OH
OH
O
4
15
15
93
90
218-220 217-219
[27]
OMe
O
O
2d
OMe
OMe
CHO
5
OH
O
258-260 256-258
OH
O
[
37]
MeO
OMe
O
O
2e
O
O
CHO
O
O
6
7
OH
O
15
15
94
97
256-257 254-257
37]
OH
O
[
O
O
2f
NO2
NO
2
OH
O
OH
O
238-240 238-239
36]
[
CHO
O
2
O
g
p o s s e s s a n e x c e ll en t ac t iv i ty ag ai n st bo t h Raillietina di ff e r en t be nz a lde hy des sub sti tut ions. I n th e pr e se nt
60
a n d Syphacia p a ra si t es . Th es e fin di n g l ed us to st udy, a lm ost a ll syn the si ze d bi sc oum ar i ns s howe d
s y n th e s iz e a s e rie s o f bi s co uma r in d eri v at iv es, wit h si gnifi c a nt a ct ivi ty a ga ins t R. echinobothrida, but only

J. Chem. Sci. (2 0 2 1 ) 13 3: 16
Table 2. c o nt i n u e d
P age 9 of 15 16
CHO
NO
NO
2
OH
O
OH
8
9
15
15
95
90
202-205 202-205
[27]
2
O
O
O
O
2h
CHO
OH
OH
OH
O
OH
252-254 253-254
[35]
O
O
2i
CN
CHO
1
1
0
1
OH
O
15
15
96
95
262-264 261-263
OH
O
[37]
O
CN
O
O
2j
F
CHO
F
OH
O
215-216 215-216
39]
OH
O
[
O
2k
Br
CHO
Br
1
2
OH
O
15
15
93
94
268-269 266-268
27]
OH
O
[
O
O
2l
Br
CHO
OH
O
13
OH
O
253-255 252-254
36]
[
O
Br
O
2m
m o de ra t e to lo w ef fic ac y ag ai n st S. obvelata. The ne m at ode c uti cl e a ct a s a r es tr ic ti on f or pa s siv e
o b s e rv e d d if fe re n ce s i n t he ac t iv i ty of co m poun ds tr a nsp or t. W hi le li poph ili c m oie ti es c an pa s siv el y
a g a in s t tw o te s t p ar as i te s co ul d be at t ri b ut ed to th e di ff us e th ro ugh th e m em br a ne , th e poo r li pid solu bility
d i f fe re n c es in th e d ru g d if fu si o n ca pa ci t y of th e two of io nise d m oie ti es a re e xc lud ed f r om suc h dif f u-
6
1 ,6 2
h e l m in th s p e c ie s . W hi l e Raillietina, wh ic h i s a c es - si on.
Thi s ju sti fic a tio n bod es we ll wit h ou r e a r lie r
6
0
t o d e, h a s a n o u te r bo d y su r fa ce ca l le d t eg ume n t whi ch ob ser va t ion, whe r e we not e d th at tr i sub sti tuted
a l lo ws s o lu t e s to cr os s via t ra ns -e pi t he l ia l t ra nsp or t. m et ha ne be a ri ng 4- hy dr oxyc ou ma ri n a nd 1,3 -dim e thyl
On th e o th e r h a nd , Syphacia p oss es se s a c om ple x ur a ci l we r e po te nt a ga ins t S. obvelata.
c u t i c le th a t u s u a ll y hi n de rs a f re e pa ss ag e of la r ge The st ru ct ur e– ac t ivi ty st udie s on syn the si ze d c om-
m o l e c u le s . It is be l ie ve d t ha t t he l ip i d ba rr i ers in th e po unds r ev ea l ed th at whe n sub sti tut ion in the

1
6
Pa g e 1 0 o f 1 5
J. Chem. Sci. (2 021) 1 33: 16
Table 2. c o nt i n u e d
Cl
CHO
Cl
1
4
15
97
257-259 258-259
27]
OH
O
OH
O
[
O
O
2n
CHO
Cl
Cl
OH
O
OH
1
1
5
6
15
15
96
97
202-204 203-204
[27]
O
O
O
2o
Cl
NO2
CHO
OH
O
250-252 249-251
Cl
OH
O
NO
2
[
29]
O
O
2p
OMe
Cl
CHO
Cl
1
7
OH
O
15
93
248-250
NA
OH
O
MeO
O
O
2q
CHO
OH
1
8
OH
15
95
265-266 264-265
[39]
O
O
O
O
2r
OH
OH
O
1
9
CHO
45
89
118-120 119-123
O
O
O
2s
[
38]
a
R
e
a
c
t
i
o
n
c
o
n
d
i
t
i
o
n
s
:
a
l
d
e
h
y
d
e
(
1
m
m
o
l
)
,
4
-
h
y
d
r
o
x
y
c
o
u
m
a
r
i
n
(
2
m
m
o
l
)
a
n
d
1
(
0
.
1
m
m
o
l
)
.
b
I so l a te d y i el d .
c o mp o u n d is wi th an el e ct ro n- wi t hd rawi n g mo i et y, th e ph eny l r ing , sho wed a n e ffi c a cy th at wa s a lmos t
a ct i v ity o f th e co mp ou nd g ot en ha nc ed , whi le th e c om pa ra bl e to th at of th e r ef e r en ce dr ug , i.e ., the
p re s e n c e o f a n el e ct ro n- d on at in g gr o up l e d to a m or ta lit y of Raillietina wor m s in on ly a bout 2 h. I n
re d u c ti o n in th e e ffi ca cy o f t he co mp ou nd . Li kewi se , c ont ra st , th e sub sti tut ion wit h a m et hoxy gr oup
t h e c o mp o u n d s w it h b ro mo, ch l or o, cy an o, flu or o a nd sho wed a de c re a se in th e e ffi c a cy of th e c om pound.
n i t ro s u b s tit u e nt s , i rr es pe ct iv e o f t he ir po si t i on in th e F ur the r , a c om poun d li ke 2q, whi ch ha s both a n

J. Chem. Sci. (2 0 2 1 ) 13 3: 16
P age 11 of 15 16
O
NHPh
HN
N
H
HN
O
O
S
H
HN
HN
NH
1
RCHO
N
R= CH R
O
S
2
NH
H
R
N
O
Ph
R1
HN
R
H
O
N
H
HN
(A)
S
PhHN
C)
1
HN
(
O
O
R
S
R= Ar
O
O
HN
Ph
S
NHPh
NH
O
O
O
H
N
(
B3)
NHPh
N
H
N
H
BISCOUMARIN
N
N
R
R
S
O
O
O
HO
O
H
H
O
O
O
O
H
(B2)
(B1)
Scheme 2. P ro po s ed m ec han i s m f or th e s ynt hes i s of bi s c oum a ri n us i ng L -p rol i ne der iv ati v e as cat al ys t .
e l ec tr o n -wi t h d ra wi ng g ro up an d an el e ct ro n- do nati ng of th e syn the si ze d bi sc oum ar i ns a nd un der st a nd the ir
g ro u p in it s a rc h ite ct ur e sh owe d a sh i ft i n i ts a ct ivi ty po ssib le in te ra c ti ons, m ole c ula r do cki ng si mul ati on of
t o w a rd s th e d ir e c ti o n di c ta t ed by t he d ona t in g gr ou p, a ll th e c om poun ds ha ve be e n c ar r ie d ou t a gai nst b-
6
3
t h u s d e c re a s in g th e ac t iv i ty of t he co mp ou nd . It is a lso tu buli n ( pdb id : 1oj 0) . Ana ly sis of th e m ol ec ul ar
n o t ew o rth y h e re t ha t t he p res en ce of t wo e le ct r on- doc ki ng si mul a tion sho ws th at a ll th e c om poun ds ( 2a–
wi t h d ra wi n g g ro u p s i n t he co mp ou nd , as i n co mpo und 2s) bi nd ve r y st ro ngly wit h th e a mi no a ci d r e si due
2
p, d o e s n o t e n h an ce t he ac t iv i ty of co mp ou nd th an in side th e a ct ive si te of th e b- tub uli n ( Ta ble 3 ) .
t h o se in th e c o mp ou nd wi th o nl y on e el e ct ro n- wit h-
d ra win g mo i e ty in t he ir st r uc tu re .
Am ong a ll th e c om poun ds, c om poun d 2a a nd 2j
sho w th e hi ghe st bi ndin g in te ra c ti on of -9.2 5 kc a l/-
m ol a nd -9.0 3 kc a l/m ol wit h th e pr ot ei n r ec e ptor .
Apa r t f r om 2j, th e c om poun ds 2k, 2l, 2m, 2n a nd 2o
a lso sho w e ff e c tiv e a ffi ni ty to war d th e a ct ive site of b-
tu buli n wit h a do cke d sc or e of -8.3 3, -8.7 4, -8.67,
3
. 2 Molecular docking
M o le c u la r d o c k in g si mu l at io n i s an at t ra ct i ve pl at fo r m
i n th e fi e ld o f ra ti o na l dr u g de si g n an d d is co ver y. Thi s
m e t h o d is wi d el y us ed i n t he p red i ct io n o f t he li ga nd
c o n fo rm a ti o n a n d i ts or i en ta ti o n i n t he ac t iv e si te of
t h e re c e p to r. M o le cul a r do ck i ng of an t he lm in ti c dr ug
wi t h b-t u b ul in to st u dy t he ac t iv i ty by d ru g- tub uli n
-
8.0 3 a nd -8.3 0 kc a l/m ol , r es pe ct ive ly , in di ca t ing
th at th e c om poun ds ha vi ng e le ct r on- wit hd ra wi ng
gr ou p e xhi bit s goo d e ffi c a cy . W he r ea s c om pounds
wit h a n e le ct r on- do nati ng gr ou p sho w lo wer bind ing
a ffi ni ty a s obs er ve d f r om our do cki ng si mul ati on 2b
(-7.1 1 kc a l/m ol ) a nd 2s ( -7.2 7 kc a l/m ol ). The
63
i n t e ra c tio n is a lre a dy p ro ven be ca us e i nh ib i ti o n of b-
t u b ul in o f th e h e lmi n th s ca n se ve re ly af f ect t he ir vi ta l
c el l u la r fu n c ti o n s su ch as mi t os is , mo ti l i t y, a nd
doc ki ng r es ult s a re in go od a gr ee m en t w ith the
e xpe r im en ta l st udy. The hi ghe r bi ndin g e ner gy of
th es e c om poun ds to war ds ta r ge t pr ot ei n c a n be
a ttr i bute d to th ei r st er i ca ll y unh ind er e d st ru ct ur e a nd
6
4
–
6
6
t ra ns p o rt.
T o r at io na l iz e t he an t he lm in ti c a ct ivi ty

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6
Pa g e 1 2 o f 1 5
J. Chem. Sci. (2 021) 1 33: 16
Table 3. Do c ked s cor e of t he t es t com p ound s wi th t he b-
t ubul i n.
C om pou nds
Do c ked s cor e i n k ca l /m o l
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
- 9. 25
- 7. 11
- 8. 03
- 8. 13
- 7. 37
- 8. 49
- 7. 99
- 7. 50
- 7. 46
- 9. 03
- 8. 33
- 8. 74
- 8. 67
- 8. 03
- 8. 30
- 8. 32
- 8. 41
- 8. 84
- 7. 27
s
Figure 2. In vitro an th elm i nti c ef fi ca cy of bi s coum ari n
d er i va t i v es a g ai n s t ( a) R. echinobothrida an d ( b) S. obve-
lata. Th e p a ra l y s is an d m or t alit y ti m e of co nt ro l wo rm fo r
r es pe ct i v e e x pe ri m en ts w as ( a) 49 .3 8 ± 1. 14 h and
5
2 . 2 ± 1 .2 7 h ; (b ) 37 .2 9 ± 2. 4 5 h an d 42 .1 8 ± 2. 13 h.
Da t a a re e x pr es s e d as m ea n ± S EM; p \ 0. 05 com par ed
wi t h c o nt ro l g ro u ps ; on e- wa y A NO V A, f ol lowe d by
Tu k e y ’ s t es t .
h i g hl y re a c ti v e fu nct i on al g ro up s l ik e cy an o, me tho xy
a n d h y d ro x y l g ro u ps wh ic h ar e i nv ol ve d i n h ydr og en
b o n d in g in t e ra c tio n. Th e bi n di ng mo de s of t wo of th e
a ct i v e c o mp o u n d s 2a an d 2j ar e sh own i n Fi gu re s 3
a n d 4.
Co m p o u n d 2a i nt er ac t s wi th t he am in o ac i d r es idu e
t h r e o n in e o f c h a in A o f ( Thr 64 A) b- tu bu li n a t a di s-
˚
t a nc e o f a b o u t 2 . 56 A . Ot he r am in o ac i d r esi du e suc h Figure 3. B e s t doc ki ng con fo rm at i on of t he com p o un d 2a
i n t he act i ve s i te of b-t ub uli n. H- bo ndi ng i nt era ct i on o f t he
com p o und wi t h am i no aci d res i du e i s s how n.
a s T h r5 8 (B ), Asp 57 ( B), Ar g6 0( B) , Ar g60 (A) ,
As p 5 7 (A), T h r64 (B ), Th r5 8( A) , Le u6 1( B) a nd
Le u6 1 (A) a ls o p la y a si g ni fic an t r ol e i n b in di ng wit h
t h e c o mp o u n d 2a i n t he ac t iv e si t e o f b- tu bul in. I n
Fi g u re 2, th e d o c k i ng ou t pu t of t he co mp ou nd 2j wit h Thr e e hyd r oge n bo ndin g in te ra c ti ons of 2j wit h a mino
˚
t h e tu b u l in re c e p to r i s pl a ced an d f ou nd t ha t a mi no a ci d r es idu es Gln 25( B ) ( 2.92 A ) , Tyr 22 (A ) ( 2.51 A )
˚
˚
a ci d re s id u e Gl n2 5( B) , Ty r2 3( A) , Tyr 23 (B ) , a nd Gln 25( A) ( 2.83 A ) ha ve be e n obs er ve d.
Ty r2 2 (A), Gl u 26 (B ), Ty r2 2( B) , Gl u2 6( A) a nd
Gl n 2 5 (A) p a rti c ip a te i n bi n di ng wi th t he co mpo und.

J. Chem. Sci. (2 0 2 1 ) 13 3: 16
P age 13 of 15 16
he nc e c an be a goo d in hibi tor . The c om poun ds 2k, 2l,
2m, 2n a nd 2o a re a lso ob ser ve d to be a go od inhi bitor
of b- tub uli n whi ch a lso a gr ee s we ll wit h th e e xpe r i-
m en ta l da ta . A de ta il ed st udy on th e m ode of a c tion of
th e bi sc oum ar i ns a nd in vivo e ffi c a cy of th e a nthe l-
m int ic c an did at es a re c ur r ent ly und er wa y a nd w ill be
r ep or te d in du e c our se of ti me .
Supplementary Information (SI)
1
1 3
The HN MR and C NMR s pec t ra of s el ect ed com p ou n ds .
Thi s m at er i al i s ava il a bl e at ww w. ia s . ac. in/ che m s ci
Acknowledgements
The ana l yt i cal s erv i ces pr ovi ded by S oph is t i cat ed An al y t -
i cal In s tr um en t at i on F aci l it y (S AI F ), No rt h Eas t e rn Hi l l
Un ive r s i ty , S hi l l ong, In di a are ack now l edged .
Figure 4. B e s t d o ck i ng co nf o r m ati on of th e co m pou nd 2j
i n t h e a ct i v e s i t e o f b- tu bul in . H -b o nd in g in te ra ct ion of t he
co mp o u n d wi t h a mi no ac id r es id ue is s ho w n.
Funding
Thi s res e arc h d i d not rec ei ve any s pec ifi c gr an t f ro m
fu ndi ng age nc y i n t he pub li c, com m e rci al , or not - fo r - pr o fit
s ect or s .
4
. Conclusions
W e h a v e e s ta b li s h ed an ex ce ll e nt me th od ol o gy f or th e
s y n th e s is o f b is c o uma r in s f ro m t he r eac t io n of 4- hy -
Compliance with ethical standards
d ro x y c o u ma r in wit h al d eh yd es us i ng L- pr ol i ne de r ive d Conflict of interest The aut ho rs dec lar e t hat t hey h av e n o
a m i d o a mi n e th i ou r ea 1 as a ca t al ys t an d he nc e con fl i ct of i nt eres t .
d e v e lo p e d a v ia b l e al t er na t iv e t o mo st l y ac i d- cat al yz ed
m e t h o d s re p o rte d i n t he l it e ra tu re . Th e pr es e nc e of
b o t h a c id i c a n d b as i c ca t al yt ic si t es i n t he bi f un c tio na l
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