2-Alkyl(aryl)-quinazolin-4(3H)-thiones, 2-R-(quinazolin-4(3H)-ylthio)carboxylic acids and amides: synthesis, molecular docking, antimicrobial and anticancer properties

Figures & data

Scheme 1. Synthesis of 2-R-quinazolin-4(3H)-thiones and their derivatives.

Scheme 2. Synthesis of 3-R-quinazolin-4(3H)-thiones.

Scheme 3. Synthesis of 2-R-quinazolin-4(3H)-thiones.

Scheme 4. Synthesis of (2-R-quinazolin-4(3H)-ylthio)acetic acids.

Scheme 5. Synthesis of the (2-R-quinazolin-4(3H)-ylthio)carboxylic acids amides.

Figure 1. Interaction of 2-(2-methyl-quinazolin-4-ylthio)-N-phenylpropionamide (4.6) (A) and reference (7-(pentan-3-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine) (B) into the DHFR binding site.

Table 1. The obtained scoring functions of the investigated compounds and (7-(pentan-3-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine) into DHFR binding site.

Cmpd	Consensus Score	Shapegauss	PLP	Chemgauss2	Chemgauss3	Chemscore	OEChemscore	Screenscore	CGO	CGT	Zapbind
4.6	82	−378.765	−49.6334	−44.7116	−60.8656	−20.527	−33.3789	−116.047	−218.186	−0.43637	−22.6468
4.7	86	−444.152	−50.459	−49.3208	−60.7651	−20.6596	−34.9882	−121.381	−190.051	−0.32638	−26.0352
Reference	86	−308.194	−51.2794	−46.1962	−64.3525	−21.2196	−28.2021	−120.31	−351.28	−0.95831	−8.45465
4.3	92	−381.148	−49.2852	−46.3099	−59.078	−22.1063	−34.3712	−109.501	−208.71	−0.40294	−22.3413
4.5	97	−381.592	−47.7807	−45.2465	−68.0848	−18.4502	−34.1904	−120.006	−197.684	−0.42593	−22.6365
3.6	108	−383.317	−46.208	−44.6148	−62.5484	−17.9078	−30.9478	−102.223	−226.669	−0.49999	−19.3994
4.4	114	−365.394	−46.6807	−42.1459	−57.7325	−18.6133	−30.0201	−114.61	−209.083	−0.47499	−23.6368
3.4	137	−354.584	−43.5951	−40.4575	−57.537	−17.6772	−30.2581	−114.387	−227.122	−0.53644	−17.5635
4.2	137	−331.913	−44.9021	−37.9129	−46.694	−18.226	−27.8546	−109.7	−245.288	−0.56868	−19.1514
4.8	139	−360.515	−49.4909	−44.2391	−57.8334	−17.6949	−29.1051	−108.545	−235.902	−0.46207	−16.0701
2.6	145	−348.186	−49.9596	−40.3333	−53.3965	−20.8559	−32.1831	−120.94	−186.402	−0.44206	−17.7927
4.1	147	−345.766	−51.1229	−42.2129	−53.5865	−20.8751	−31.1928	−127.393	−195.133	−0.43923	−14.7374
3.5	157	−356.475	−48.9562	−44.038	−58.2667	−18.0081	−32.4152	−122.376	−200.883	−0.41885	−10.7625
2.5	197	−289.134	−41.4663	−35.6895	−52.4105	−15.6978	−25.8349	−111.403	−198.767	−0.45301	−19.2544
2.13	200	−259.853	−40.9669	−33.8891	−42.4025	−16.9804	−24.039	−96.9218	−272.537	−0.73395	−18.7643
3.9	215	−300.149	−38.0297	−36.7167	−42.1042	−13.8311	−27.2424	−95.5493	−240.888	−0.59124	−17.0203
2.17	220	−347.948	−40.6094	−41.0362	−58.406	−15.1547	−27.4	−93.372	−101.988	−0.21461	−22.1789
2.14	223	−299.186	−41.2863	−34.2701	−46.2202	−16.6175	−25.0826	−101.669	−195.767	−0.45753	−17.8969
2.15	225	−293.334	−40.2826	−33.639	−47.1476	−16.0805	−24.8425	−103.112	−197	−0.46266	−17.6947
4.9	234	−372.463	24.61172	−45.7289	−55.1096	−15.4709	−28.1221	−26.1088	−160.542	−0.35169	−20.3654
2.16	239	−286.71	−40.4509	−33.5012	−46.304	−15.0294	−24.6116	−102.597	−197.935	−0.46985	−17.4272
2.12	242	−264.66	−37.1178	−34.8203	−52.7886	−14.3724	−22.2174	−92.4593	−227.895	−0.70836	−13.4663
2.18	250	−282.787	−32.8939	−33.8284	−39.9133	−14.785	−−25.2986	−89.7601	−218.89	−0.49911	−19.1477
2.4	253	−282.489	−39.6817	−32.4522	−45.3545	−15.2888	−24.9071	−102.492	−189.837	−0.46683	−17.0605
2.9	256	−279.662	−37.329	−34.5317	−40.7148	−15.3446	−24.0937	−86.958	−212.897	−0.61779	−14.6992
3.2	276	−256.281	−37.0266	−30.4889	−39.6976	−13.9405	−21.1586	−94.9782	−225.681	−0.66529	−16.4408
2.7	281	−245.564	−33.1216	−29.8359	−35.8302	−14.2575	−22.9476	−82.0469	−226.679	−0.53643	−19.9704
2.11	282	−276.842	−38.6947	−31.4477	−42.7806	−14.258	−23.472	−96.1665	−180.632	−0.46416	−17.242
3.7	284	−286.732	−28.7227	−32.8977	−29.3642	−15.1515	−24.506	−64.3374	−218.546	−0.36965	−22.1967
2.10	288	−263.681	−32.4705	−31.9649	−37.644	−13.4627	−22.2012	−84.7462	−232.8	−0.59302	−15.9064
3.8	307	−307.998	−33.4153	−39.6585	−44.5068	−10.1369	−19.2077	−86.2238	−149.599	−0.37068	−16.8518
3.1	307	−238.767	−34.8311	−28.7247	−37.8476	−12.8009	−20.9541	−90.6225	−216.915	−0.66458	−15.8733
3.3	311	−268.889	−32.1917	−38.5509	−41.7444	−12.482	−22.906	−78.2142	−194.199	−0.5021	−7.9952
2.8	347	−231.165	−34.8882	−29.3037	−36.1957	−9.09227	−16.0344	−85.5844	−185.563	−0.56516	−13.4571
2.3	364	−260.234	−33.4146	−29.595	−42.376	−12.449	−21.6917	−82.2969	−99.7401	−0.28716	−14.1796
2.2	393	−196.074	−24.9307	−22.9715	−35.0098	−9.1122	−16.4791	−70.2144	−107.419	−0.29593	−16.2219

Table 2. Microorganisms’ growth inhibition zones (in mm).

Compound	Conc. (µg/disk)	Staphylococcus aureus	Enterococcus aeruginosa	Klebsiella pneumonia	Candida albicans
2.1	100	15	11	11	6*
2.2	100	6	6	6	23
2.3	100	6	6	6	16
2.4	100	15	10	10	8
2.8	100	9	6	6	6
2.9	100	11	6	6	18
2.10	100	6	6	6	13
2.11	100	6	6	6	15
2.15	100	6	6	6	10
Gatifloxacin	5	30	−**	−	−
Gemifloxacin	5	30	−	−	−
Moxifloxacin	5	31	−	−	−
Ceftriaxone	30	33	−	25	−
Nystatin	100	−	−	−	21
Ampicillin	10	22	16	−	−

All statistical analysis of the results was carried out using the “Biostatistica” software (p ≤ 0.05).

*6 mm − diameter paper disk.

**Not investigated.

Figure 2. Interaction of 2-styryl-(quinazolin-4-ylthio)acetic acid (3.7) (A) and Silmitasertib (CX-4945) (B) into the binding site of protein kinase CK2.

Table 3. The obtained scoring functions of the investigated compounds and Silmitasertib into CK2 kinase binding site.

Cmpd	Consensus score	Shapegauss	PLP	Chemgauss2	Chemgauss3	Chemscore	OEChemscore	Screenscore	CGO	CGT	Zapbind
3.7	46	−465.545	−57.0443	−52.0457	−89.526	−22.8763	−38.2368	−146.183	−272.397	−0.5101	−17.8824
4.9	65	−447.211	−54.6976	−47.7201	−75.0627	−22.0093	−35.6513	−134.385	−263.625	−0.4875	−19.4444
3.6	100	−428.575	−50.8626	−46.2184	−84.1132	−19.661	−31.9269	−122.944	−281.953	−0.51936	−15.6018
4.4	111	−442.753	−56.5359	−51.9282	−79.1107	−24.8452	−38.2661	−155.028	−214.612	−0.38081	−12.7306
3.5	113	−423.283	−46.3807	−45.3975	−77.7719	−19.6203	−32.312	−119.811	−269.899	−0.50498	−17.9316
4.1	114	−435.422	−48.305	−47.4608	−66.9817	−19.5518	−35.4336	−118.385	−269.485	−0.45643	−21.7419
4.7	116	−452.331	−48.8969	−47.4851	−67.022	−19.8292	−33.0239	−115.513	−258.918	−0.39834	−22.7315
3.9	125	−407.418	−50.5678	−43.645	−78.0435	−19.8355	−30.0673	−125.964	−244.859	−0.47028	−18.7362
4.3	125	−438.655	−47.5173	−48.4867	−73.9937	−18.5955	−33.0863	−125.574	−238.485	−0.37643	−19.7773
3.4	131	−390.288	−52.0469	−46.6193	−70.9293	−21.6011	−33.7218	−113.403	−245.244	−0.45564	−19.777
4.6	137	−400.893	−48.0687	−43.0718	−70.9628	−18.3473	−31.2201	−115.011	−268.464	−0.46281	−23.5911
Silmitasertib	158	−424.616	−44.4712	−47.3726	−69.2785	−18.7694	−32.451	−118.674	−244.346	−0.37861	−19.8628
4.8	168	−421.062	−45.1238	−45.1304	−67.259	−18.014	−30.1503	−115.397	−267.213	−0.48533	−18.925
2.13	174	−379.789	−49.9054	−40.2089	−75.7726	−18.8896	−28.2063	−115.153	−230.579	−0.46066	−19.2743
2.7	177	−388.947	−46.1489	−40.0884	−71.9881	−19.3879	−31.2235	−112.757	−253.82	−0.48786	−17.8278
2.5	185	−379.177	−44.743	−40.5407	−70.1908	−19.7693	−31.3653	−111.778	−234.62	−0.51387	−18.2424
4.2	187	−398.286	−42.2567	−43.9281	−65.9785	−18.0202	−30.0671	−110.607	−289.325	−0.48154	−19.2192
2.14	200	−259.853	−40.9669	−33.8891	−42.4025	−16.9804	−24.039	−96.9218	−272.537	−0.73395	−18.7643
2.15	215	−359.284	−41.9247	−37.9216	−70.7715	−17.1314	−26.9806	−113.381	−247.599	−0.49254	−21.8732
2.17	225	−384.701	−39.4418	−44.3643	−68.6724	−11.178	−27.1451	−113.632	−273.045	−0.53468	−17.3226
2.16	226	−367.321	−49.5066	−39.297	−71.1119	−17.1016	−28.7606	−113.392	−223.74	−0.44982	−18.5348
4.5	243	−400.059	−43.1326	−44.8307	−51.2566	−19.4939	−30.6285	−114.266	−220.905	−0.37854	−12.3272
2.11	250	−374.852	−52.315	−38.1648	−69.8586	−17.1932	−28.4853	−109.82	−203.502	−0.40935	−17.2089
2.10	272	−359.428	−46.3294	−40.4289	−59.6429	−16.6666	−29.195	−95.8228	−226.098	−0.45694	−16.971
2.6	279	−348.078	−41.9709	−36.5865	−65.4811	−16.9829	−28.2629	−104.365	−205.341	−0.36445	−23.0116
2.9	287	−344.132	−42.0194	−35.3252	−61.3411	−16.4878	−25.7006	−105.813	−206.169	−0.41606	−20.1194
3.2	290	−331.338	−37.2939	−33.9678	−65.3822	−15.1261	−23.7235	−95.9809	−222.752	−0.48607	−20.6174
3.8	302	−330.22	−38.0283	−36.3433	−71.1171	−13.3303	−20.9295	−102.169	−227.065	−0.43846	−18.7044
2.4	306	−329.269	−42.851	−34.4855	−59.3032	−17.1053	−27.5289	−106.138	−186.669	−0.3445	−19.1691
3.3	313	−340.33	−39.5097	−37.3865	−58.6646	−15.0863	−27.1866	−114.204	−213.336	−0.3974	−3.82986
2.12	344	−319.216	−39.4209	−33.4432	−56.3152	−14.9212	−22.6947	−100.03	−171.279	−0.33309	−19.5219
3.1	348	−329.32	−41.1729	−37.3324	−56.1612	−15.4284	−26.6064	−105.983	−170.162	−0.30434	−16.2156
2.3	359	−284.88	−40.0202	−28.3876	−56.6993	−14.4478	−23.0104	−98.8193	−161.087	−0.34059	−18.7
2.18	360	−318.385	−33.8189	−32.8457	−49.0541	−12.8196	−22.0651	−88.9445	−190.158	−0.29216	−22.9582
2.8	366	−287.948	−40.3914	−30.1253	−58.4542	−13.0625	−21.1519	−97.3175	−171.226	−0.34107	−17.5733
2.2	400	−268.66	−35.0508	−26.1141	−51.8065	−12.9322	−21.0005	−85.8291	−149.89	−0.31695	−17.199
2.1	404	−268.407	−35.9859	−27.4171	−53.8422	−13.4993	−20.3355	−90.374	−124.304	−0.27049	−14.629

Table 4. Percentage of in vitro tumor cell lines growth with investigated substances in 10 µM.

	Compound/Growth percent
Subpanel tumor cell lines	2.5	2.8	2.18	3.8
Leukemia
CCRF-CEM	95.86	102.64	18.75	102.67
HL-60(TB)	98.58	97.17	97.02	108.99
K-562	nt	110.42	98.36	107.52
MOLT-4	105.14	117.38	90.50	116.67
RPMI-8226	nt	89.50	99.12	89.67
SR	95.49	108.57	91.75	150.08
Non-small cell lung
A549/ATCC	104.38	95.59	96.01	96.80
EKVX	105.26	109.52	91.75	112.46
HOP-62	106.59	101.31	85.56	99.07
HOP-92	90.95	97.95	97.09	108.30
NCI-H226	102.59	113.93	114.06	101.31
NCI-H23	nt	96.66	99.19	89.87
NCI-H322M	103.03	107.47	114.93	96.83
NCI-H460	110.50	107.59	106.45	106.90
NCI-H522	92.96	88.20	87.26	92.36
Colon cancer
COLO 205	131.96	101.98	111.56	113.19
HCC-2998	97.13	102.03	104.46	77.72
HCT-116	106.59	100.25	101.75	100.03
HCT-15	110.56	103.04	107.44	102.97
HT29	107.08	106.35	nt	104.49
KM12	117.43	114.67	106.26	113.99
SW-620	113.17	110.06	105.87	102.53
Renal cancer
786-0	105.32	106.86	103.03	100.27
A498	80.24	84.51	96.78	54.81
ACHN	105.30	98.83	94.67	102.70
CAKI-1	87.12	73.23	87.51	160.10
RXF 393	120.11	108.49	105.43	112.15
SN12C	104.86	111.03	101.68	95.31
TK-10	109.08	111.71	143.35	102.22
105 to	nt	nt	nt	nt
Prostate cancer
PC-3	96.85	103.10	89.33	98.05
DU-145	nt	146.23	123.87	147.82
Breast cancer
MCF7	102.97	99.89	92.18	100.24
MDA-MB-231/ATCC	95.11	123.36	89.18	107.68
HS 578T	103.99	111.23	85.79	109.87
BT-549	98.85	106.65	100.39	94.03
T-47D	101.89	102.96	92.97	107.69
MDA-MB-468	116.17	91.46	101.97	88.95
MDA-MB-435	107.35	111.08	95.21	107.42
NCl/ADR-RES	106.74	102.43	103.48	91.31
Ovarian cancer
IGROV1	112.61	71.97	112.81	101.62
OVCAR-3	115.31	140.99	117.06	146.62
OVCAR-4	109.61	99.33	103.00	97.45
OVCAR-5	108.40	100.55	107.94	83.61
OVCAR-8	100.66	96.66	104.94	104.34
NCI/ADR-RES	106.74	102.43	103.48	91.31
SK-OV-3	113.26	102.10	100.75	101.22
Melanoma
LOX IMVI	nt	97.13	109.57	97.75
MALME-3M	117.22	85.15	109.47	101.16
M14	97.74	101.45	111.92	100.37
SK-MEL-2	nt	102.81	125.84	104.18
SK-MEL-28	118.60	118.36	107.66	97.34
SK-MEL-5	100.44	99.46	87.39	109.72
UACC-257	107.03	94.13	99.95	99.36
UACC-62	105.96	121.79	84.18	99.53
MDA-MB-435	nt	111.08	95.21	107.42
CNS cancer
SF-268	109.50	118.94	103.45	171.12
SF-295	98.53	123.25	108.42	109.27
SF-539	101.83	98.21	101.33	102.60
SNB-19	106.25	89.85	104.44	94.12
SNB-75	99.55	89.19	84.82	64.28
U251	101.57	95.33	101.21	102.51
Mean of data	104.38	103.49	99.96	103.00
Delta of data	29.33	31.52	81.21	85.99
Range of data	56.91	74.26	124.60	154.11

nt – Not tested.